Role of ERK1/2 activation and nNOS uncoupling on endothelial dysfunction induced by lysophosphatidylcholine.
Atherosclerosis
; 258: 108-118, 2017 03.
Article
em En
| MEDLINE
| ID: mdl-28235709
ABSTRACT
BACKGROUND AND AIMS:
Lysophosphatidylcholine (LPC) - a main component of oxidized LDL - is involved in endothelial dysfunction that precedes atherosclerosis, with an increased superoxide anions and a reduced NO production via endothelial NO synthase (eNOS) uncoupling. However, there is no evidence about the mechanisms involved in neuronal NOS (nNOS) uncoupling. Extracellular signal-regulated kinase (ERK) is related to the control of NO production and inflammatory gene transcription activation in atherosclerosis. Our aim was to investigate the role of nNOS/ERK1/2 pathway on endothelial dysfunction induced by LPC, in mouse aorta and human endothelial cells.METHODS:
Thoracic aorta from wild type mice was used to perform vascular reactivity studies in the presence or absence of LPC. Human endothelial cells were used to investigate the effect of LPC on expression of nNOS and his products NO and H2O2.RESULTS:
LPC reduced acetylcholine (ACh)-induced vasodilation in mouse aorta (EmaxCT/LPC = â¼95 ± 2/62 ± 3%, p = 0.0004) and increased phenylephrine-induced vasoconstriction (EmaxCT/LPC = â¼4 ± 0,1/6 ± 0,1 mN/mm, p = 0.0002), with a reduction in NO (fluorescence intensityCT/LPC = 91 ± 3/62±2 × 103, p = 0.0002) and H2O2 (fluorescence intensityCT/LPC = â¼16 ± 0,8/10 ± 0,7 × 103, p = 0.0041) production evocated by ACh. An inhibition of nNOS by TRIM (EmaxCT/CT+TRIM = â¼93 ± 1/43 ± 3%, p = 0,0048; EmaxLPC/LPC+TRIM = â¼62 ± 3/65 ± 3%) or H2O2 degradation by catalase (EmaxCT/CT+cat = â¼93 ± 1/46 ± 2%, p < 0,001; EmaxLPC/LPC+cat = â¼62,8 ± 3,2/60,5 ± 4,7%) reduced the relaxation in the control but not in LPC group. PD98059, an ERK1/2 inhibitor, abolished the increase in vasoconstriction in LPC-treated vessels (EmaxLPC/LPC+PD = â¼6 ± 0,1/3 ± 0,1 mN/mm, p = 0.0001). LPC also reduced the dimer/monomer proportion and increased nNOSser852 phosphorylation.CONCLUSIONS:
LPC induced nNOS uncoupling and nNOSSer852 phosphorylation, reduced NO and H2O2 production and improved superoxide production by modulating ERK1/2 activity in human and murine endothelial cells.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Aorta Torácica
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Vasoconstrição
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Vasodilatação
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Lisofosfatidilcolinas
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Proteína Quinase 1 Ativada por Mitógeno
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Células Endoteliais
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Proteína Quinase 3 Ativada por Mitógeno
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Óxido Nítrico Sintase Tipo I
Limite:
Animals
Idioma:
En
Revista:
Atherosclerosis
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Brasil